The NF-kappaB transcription factor has recently emerged as a critical regulator of cell fate. In most cases, NF-kappaB stimulates expression of a set of genes which promote both cell survival and proliferation. Accordingly, dysregulated NF-kappaB activity has been identified as a major contributing factor in the pathogenesis and progression of various cancers. We have recently demonstrated that two independent chromosomal translocations in MALT lymphoma, which target distinct sets of genes, actually impact the same intracellular signal transduction pathway and lead to a common physiologic effect, a dramatic and unregulated induction of NF-kappaB activity. Together, these two translocations are present in the majority of MALT lymphomas, suggesting that the induction of NF-kappaB plays an important role in the pathogenesis of this disease. The long-term objectives of this proposal are to further characterize the protein products of the genes targeted by these two re-current chromosomal translocations. With one translocation, t(11;14), expression of the Bcl10 gene is inappropriately enhanced. Bcl10 binds to a novel protein, MALT1, and activates a caspase-like, cysteine protease domain within this protein. The second translocation, t(11;18), results in the creation of a novel fusion protein, API2-MALT1. Our work has demonstrated that in both cases, the MALT1 cysteine protease domain is activated, an event which leads to the unregulated induction of NF- kappaB. In addition to studying the molecular mechanisms whereby these proteins activate NF-kappaB, we will develop a mouse model for MALT lymphoma in order to study the contribution that NF-kappaB activity makes toward the development and progression of the disease. Inhibitors of NF-kappaB will also be explored as potential novel therapeutic tools. We have three Specific Aims: (1) Identify targets of the MALT1 protease and their relevance to NF-kappaB induction, (2) identify upstream signaling pathways which ultimately control MALT1 activity, and (3) Develop a genetic mouse model for MALT lymphoma. These aims will involve a wide range of techniques which will prepare the investigator for a career directing an independent research program.